Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor. The chemical name for allopurinol tablets is 1, 5-dihydro-4H-pyrazolo 3, 4-dpyrimidin-4-one, with a molecular weight of 136.11 g/mol. Allopurinol exhibits a solubility in water of 80.0 mg/dL at 37°C, which increases in alkaline solutions.

The scored white, flat cylindrical tablet formulation contains 100 mg of allopurinol along with inactive ingredients including corn starch, lactose monohydrate, magnesium stearate, povidone, and purified water. The scored peach, flat cylindrical tablet formulation contains 300 mg of allopurinol, with inactive ingredients comprising corn starch, FD&C Yellow No. 6 Aluminium Lake, lactose monohydrate, magnesium stearate, povidone, and purified water.

Uses and Indications

Allopurinol Tablets are indicated for the management of adult patients exhibiting signs and symptoms of primary or secondary gout, including acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy. Additionally, Allopurinol is indicated for both adult and pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are undergoing cancer therapy that results in elevated serum and urinary uric acid levels. Furthermore, it is indicated for adult patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in males and 750 mg/day in females, despite lifestyle modifications.

Limitations of use include the recommendation against the treatment of asymptomatic hyperuricemia with Allopurinol Tablets.

Dosage and Administration

For the management of gout, patients with normal kidney function should initiate treatment with 100 mg orally once daily. The dosage may be increased by 100 mg weekly increments until a target serum uric acid level of 6 mg/dL or less is achieved, with a maximum allowable dosage of 800 mg daily. For patients with impaired kidney function, the initial dosage is 50 mg orally once daily, with titration recommendations to be followed as outlined for renal impairment until the target serum uric acid level is reached.

In cases of hyperuricemia associated with cancer therapy, adult patients may be prescribed a dosage range of 300 mg to 800 mg orally daily. For pediatric patients, the recommended dosage is 100 mg/m² orally every 8 to 12 hours, not exceeding a maximum of 800 mg per day (10 mg/kg/day).

For the prevention of recurrent calcium oxalate calculi, the recommended initial dosage for patients with normal kidney function is 200 mg to 300 mg orally once daily.

For patients with renal impairment, healthcare professionals should refer to the full prescribing information (FPI) for specific dosage modifications and recommendations tailored to the patient's renal status.

Contraindications

Use of allopurinol is contraindicated in patients with known hypersensitivity to allopurinol or to any of the ingredients of allopurinol tablets. This contraindication is essential to prevent severe allergic reactions that may occur in susceptible individuals.

Warnings and Precautions

Allopurinol is associated with several significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Skin Rash and Hypersensitivity Allopurinol has been linked to serious and potentially fatal dermatological reactions. It is imperative that allopurinol tablets be discontinued immediately upon the first appearance of a skin rash or any other signs indicative of a hypersensitivity reaction.

Gout Flares Patients may experience gout flares during the initiation of allopurinol treatment. To mitigate this risk, concurrent prophylactic treatment with colchicine or other anti-inflammatory agents is recommended.

Nephrotoxicity Allopurinol may adversely affect kidney function. Therefore, patients with impaired renal function should receive lower doses of allopurinol tablets to prevent further renal compromise.

Hepatotoxicity Reversible hepatotoxicity has been reported in patients taking allopurinol. Should any signs or symptoms of hepatotoxicity arise, it is essential to evaluate liver function promptly.

Myelosuppression There have been reports of bone marrow suppression associated with allopurinol use. Monitoring for signs of myelosuppression is advised.

Potential Effect on Driving and Use of Machinery Patients taking allopurinol may experience drowsiness, somnolence, or dizziness. Caution should be exercised when driving or operating machinery until the individual’s response to the medication is known.

Laboratory Tests In the event that signs and symptoms of hepatotoxicity develop, it is crucial to evaluate liver function to ensure patient safety and appropriate management.

Healthcare professionals are encouraged to remain vigilant regarding these warnings and to monitor patients accordingly to mitigate risks associated with allopurinol therapy.

Side Effects

Patients receiving allopurinol may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Most commonly reported adverse reactions include nausea, diarrhea, and an increase in liver function tests, with an incidence greater than 1%. These reactions are generally mild but should be monitored.

Serious adverse reactions associated with allopurinol include skin rash and hypersensitivity, which can lead to serious and sometimes fatal dermatological reactions. It is crucial to discontinue allopurinol tablets at the first appearance of a skin rash or any other signs of hypersensitivity. Gout flares may also occur during the initiation of treatment; therefore, concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended to mitigate this risk.

Nephrotoxicity is another serious concern, as allopurinol may affect kidney function. Patients with decreased kidney function require careful dose adjustments to avoid potential complications. Hepatotoxicity has been reported, with cases of reversible liver damage occurring; thus, it is important to evaluate liver function if any signs or symptoms of hepatotoxicity develop. Additionally, myelosuppression has been noted, indicating a risk of bone marrow suppression in some patients.

Patients should also be aware of the potential effects of allopurinol on driving and the use of machinery, as drowsiness, somnolence, and dizziness have been reported.

It is important to note that allopurinol is contraindicated in patients with known hypersensitivity to allopurinol or any of its ingredients.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

Packaging & NDC

The table below lists all NDC Code configurations of Allopurinol, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of allopurinol have been established in approximately 200 pediatric patients with leukemia, lymphoma, and solid tumor malignancies undergoing cancer therapy that leads to elevated serum and urinary uric acid levels. The efficacy and safety profile in this population is comparable to that observed in adults.

However, the use of allopurinol tablets for the treatment of signs and symptoms of primary or secondary gout in pediatric patients has not been established. Additionally, its safety and effectiveness have not been determined for managing recurrent calcium oxalate calculi or in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients, particularly those aged 65 and older, may require special consideration when initiating treatment with allopurinol, especially in the presence of renal impairment. For these patients, the initial dosage should be set at 50 mg orally daily, with subsequent dose increases made cautiously in 50 mg/day increments every 2 to 4 weeks until the target serum uric acid level is achieved. This gradual titration is essential to minimize the risk of serious adverse reactions associated with the medication.

Close monitoring of kidney function is critical in geriatric patients with chronic kidney disease who are starting allopurinol therapy. If there are any persistent abnormalities in kidney function, it may be necessary to decrease the dosage or discontinue the medication altogether. While the maximum dosage for patients with varying degrees of renal impairment has not been established based on different estimated glomerular filtration rate (eGFR) levels, it is imperative to remain vigilant regarding renal status throughout treatment.

Elderly patients with a history of kidney disease, including chronic kidney disease or kidney stones, may be at an elevated risk for further deterioration of kidney function or acute kidney injury due to xanthine calculi during allopurinol therapy. Therefore, frequent monitoring of kidney function is advised, particularly during the initial stages of treatment.

Additionally, it is recommended that patients increase their fluid intake to at least 2 liters per day to maintain hydration and help prevent the formation of kidney stones.

Furthermore, the presence of the HLA-B5801 allele has been associated with an increased risk of developing allopurinol-related hypersensitivity syndromes, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN). Screening for the HLA-B5801 allele should be considered in populations with a known high prevalence of this genetic marker prior to initiating treatment. Allopurinol is not recommended for patients who test positive for HLA-B*5801 unless the potential benefits clearly outweigh the associated risks.

Pregnancy

Based on findings in animal studies, allopurinol tablets may cause fetal harm when administered to pregnant women. Adverse developmental outcomes have been observed in exposed animals, and both allopurinol and its metabolite oxypurinol have been shown to cross the placenta following maternal administration.

Limited published data on allopurinol use in pregnant women do not demonstrate a clear pattern or increase in the frequency of adverse developmental outcomes. Among approximately 50 pregnancies described in the literature, two infants with major congenital malformations have been reported following maternal exposure to allopurinol. It is important to advise pregnant women of the potential risks to the fetus.

All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Experience with allopurinol during human pregnancy has been limited, as women of reproductive age rarely require treatment with this medication. A case report from 2011 described a full-term pregnancy in a 35-year-old woman with recurrent kidney stones who took allopurinol throughout her pregnancy; the child was born with multiple complex birth defects and died at 8 days of life.

A subsequent report in 2013 provided data on 31 prospectively ascertained pregnancies involving mothers exposed to allopurinol for varying durations during the first trimester. The overall rate of major fetal malformations and spontaneous abortions was reported to be within the normal expected range; however, one child had severe malformations similar to those described in the earlier case report.

Animal studies have shown no evidence of fetotoxicity or teratogenicity in rats or rabbits treated with oral allopurinol during the period of organogenesis at doses up to 200 mg/kg/day and 100 mg/kg/day, respectively, which is approximately 2.4 times the human dose on a mg/m² basis. However, a published report in pregnant mice indicated that single intraperitoneal doses of 50 mg/kg or 100 mg/kg (approximately 0.3 or 0.6 times the human dose on a mg/m² basis) administered on gestation days 10 or 13 resulted in significant increases in fetal deaths and teratogenic effects, including cleft palate, harelip, and digital defects. It remains uncertain whether these findings represent a direct fetal effect or an effect secondary to maternal toxicity.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers. Additionally, there is no data on the potential for excretion of this medication in breast milk or its effects on breastfed infants. Healthcare professionals should consider the lack of information when advising lactating mothers about the use of this medication.

Renal Impairment

Patients with renal impairment may experience nephrotoxicity associated with allopurinol. It is essential to consider that individuals with decreased kidney function require lower doses of allopurinol tablets to mitigate the risk of adverse effects. Monitoring of renal function is recommended to ensure appropriate dosing and to prevent potential complications.

Hepatic Impairment

Patients with hepatic impairment may experience reversible hepatotoxicity. In the event that signs and symptoms of hepatotoxicity develop, it is essential to evaluate liver function promptly. Monitoring of liver function tests should be conducted to assess the extent of any hepatic compromise. Based on the evaluation, appropriate clinical decisions should be made regarding the continuation or modification of therapy in these patients.

Overdosage

In the event of an overdosage of allopurinol tablets, it is important to note that there is no specific antidote available. Healthcare professionals should be aware that both allopurinol and its active metabolite, oxipurinol, are dialyzable. However, the efficacy of hemodialysis or peritoneal dialysis in the management of an allopurinol overdose remains uncertain.

Given the lack of a specific antidote, the focus should be on supportive care and symptomatic management. Monitoring of the patient’s clinical status is essential, and appropriate interventions should be initiated based on the symptoms presented. Healthcare providers are encouraged to consult local poison control centers or toxicology experts for guidance on managing specific cases of overdosage.

Nonclinical Toxicology

No evidence of tumorigenicity was observed in male or female mice or rats that received oral allopurinol for the majority of their life spans (greater than 88 weeks) at doses up to 20 mg/kg/day, which corresponds to 0.1 and 0.2 times the maximum recommended human dose (MRHD) on a mg/m² basis in mice and rats, respectively.

Allopurinol tested negative in several genotoxicity assays, including the in vitro Ames assay, the in vitro mouse lymphoma assay, and the in vivo rat bone marrow micronucleus assay. Additionally, allopurinol administered intravenously to rats at a dose of 50 mg/kg was not incorporated into rapidly replicating intestinal DNA. No evidence of clastogenicity was observed in lymphocytes taken from patients treated with allopurinol for a mean duration of 40 months, nor in an in vitro assay with human lymphocytes.

Allopurinol oral doses of 20 mg/kg/day had no effect on male or female fertility in rats or rabbits, which corresponds to approximately 0.2 or 0.5 times the MRHD on a mg/m² basis, respectively.

Postmarketing Experience

Postmarketing experience has indicated that allopurinol tablets may be associated with an increased risk of serious and potentially fatal dermatologic reactions. Reports have included skin rash, blisters, fever, painful urination, blood in the urine, eye irritation, and swelling of the lips or mouth, as well as other signs and symptoms consistent with hypersensitivity reactions.

Additionally, gout flares have been reported during the initiation of treatment with allopurinol tablets, even in patients with normal serum uric acid levels. Nephrotoxicity has also been observed, with effects on kidney function documented in postmarketing reports. Hepatotoxicity has been noted, with signs and symptoms of liver failure such as jaundice, pruritus, bleeding, bruising, and anorexia.

Myelosuppression has been reported, characterized by signs and symptoms including infection, fever, bleeding, shortness of breath, and significant fatigue. Other adverse effects reported include drowsiness, somnolence, and dizziness in patients taking allopurinol tablets.

There are also risks of adverse effects when allopurinol tablets are used in conjunction with certain medications, including dicumarol, warfarin, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, pegloticase, theophylline, and thiazide diuretics.

Patient Counseling

Healthcare providers should advise patients to take allopurinol tablets after meals to minimize gastric irritation. In the event that a single dose is occasionally forgotten, patients should be informed that there is no need to double the dose at the next scheduled time.

It is important to inform patients that allopurinol tablets may increase the risk of serious and potentially fatal dermatologic reactions. Patients should be instructed to discontinue the medication and seek medical attention immediately at the first sign of a skin rash, blisters, fever, painful urination, blood in the urine, irritation of the eyes, swelling of the lips or mouth, or any other signs and symptoms of hypersensitivity reactions.

Patients should also be made aware that gout flares may occur during the initiation of treatment with allopurinol tablets, even if their serum uric acid levels are normal. The concurrent use of additional medications such as colchicine or other anti-inflammatory agents can help prevent gout flares. Patients should be advised to continue treatment with both allopurinol tablets and any prophylactic therapy as prescribed, even if gout flares occur. They should be reassured that it may take several months to achieve control of the flares, but that these flares typically become shorter and less severe over time.

Additionally, patients should be informed that allopurinol tablets may affect kidney function. They should be advised to increase their fluid intake during therapy, aiming for at least 2 liters of liquids per day, to stay well hydrated and help prevent kidney stones.

Patients should also be made aware of the risk of hepatotoxicity associated with allopurinol. They should report any signs and symptoms of liver failure, such as jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

Furthermore, patients should be informed about the risk of myelosuppression and should report any signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue to their healthcare provider.

Drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol tablets. Patients should be informed that the central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants. They should be advised to avoid operating automobiles or other dangerous machinery and to refrain from activities that may be hazardous due to decreased alertness when starting allopurinol tablets or increasing the dose, until they understand how the drug affects them.

Patients should also be informed of the risks of adverse effects when allopurinol tablets are used in conjunction with certain medications, including dicumarol, warfarin, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, pegloticase, theophylline, and thiazide diuretics. They should be encouraged to disclose all medications they are currently using and to follow their physician's instructions.

Pregnant women should be advised of the potential risks to a fetus and should notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with allopurinol tablets. Additionally, women should be advised not to breastfeed during treatment with allopurinol tablets and for one week after the last dose.

Storage and Handling

The product is supplied in a tight container as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F) in a dry place to maintain its integrity and efficacy. Proper storage conditions are essential to ensure the product remains within the specified parameters.

Additional Clinical Information

Patients initiating treatment with allopurinol tablets should be screened for the HLA-B5801 allele, particularly in populations with a high prevalence of this genetic marker. Screening is not recommended for patients from populations with low prevalence or for current allopurinol users, as the risk of serious skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS) is primarily associated with the initial months of therapy, independent of HLA-B5801 status.

Clinicians should counsel patients to discontinue allopurinol tablets immediately if a skin rash develops and to seek medical attention promptly. Patients are advised to continue taking allopurinol tablets and any prophylactic treatments even during gout flares, as it may take time to achieve effective control. Maintaining adequate fluid intake to ensure a urinary output of at least 2 liters per day is essential to prevent xanthine calculi formation and renal precipitation of urates, especially in those receiving uricosuric agents. Additionally, patients should be informed about the potential additive central nervous system depressant effects of allopurinol tablets with alcohol and other CNS depressants, and they should avoid operating vehicles or engaging in hazardous activities until they are aware of how the medication affects them.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Allopurinol as submitted by REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)